General

Historically, cannabinoid receptors were defined as those receptors that respond to cannabinoid drugs, such as Δ⁹-tetrahydrocannabinol (THC) derived from Cannabis sativa [14,18,38] and its biologically active synthetic analogues (see PHARMACOLOGY section below). This is because there was no known endogenous agonist when the first of these receptors was discovered in the late 1980's. Subsequently, it was found that mammalian tissues do synthesize and release compounds that can activate cannabinoid receptors. The most widely investigated of these ‘endocannabinoids’ are N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl glycerol [12,41,72], both of which are synthesized on demand in response to elevations of intracellular calcium [13]. Other compounds that may serve as endocannabinoids include N-dihomo-γ-linolenoylethanolamine, N-docosatetraenoylethanolamine, O-arachidonoylethanolamine (virodhamine), oleamide, N-arachidonoyl dopamine and N-oleoyl dopamine [52]. Endocannabinoids and their receptors constitute the ‘endocannabinoid system’. Because it is not yet clear whether these are the only endogenous agonists, the subcommittee continues to call the receptors 'cannabinoid receptors' rather than naming them after the endogenous agonists as recommended by NC-IUPHAR (see Revised NC-IUPHAR Recommendations for Nomenclature of Receptors, this edition and [52]).

Cannabinoid Receptors

The cannabinoid receptor family is denoted by the abbreviation 'CB' and receptors are numbered by their order of discovery, denoted by a numerical subscript (e.g. CB₁, CB₂). Two cannabinoid receptors have been described to date.

The CB₁ cannabinoid receptor has been cloned from rat [40], mouse [10] and human [23] tissues (97-99% amino acid (aa) sequence identity across species). Its structure is that of a seven-transmembrane domain (7TM) receptor [40] consistent with biochemical and cellular determinations of signal transduction via G proteins [11,31,34,44,62,67]. The CB₁ receptor mRNA and protein are found primarily in brain and nervous tissue [25,32,36,40].

The CB₂ cannabinoid receptor was discovered in a human leukemia HL60 library as a cDNA fragment that exhibited 68% homology with the CB₁ cannabinoid receptor, and mRNA is found primarily in immune tissue [42]. Expressed CB₂ receptor protein was shown to bind cannabinoid and aminoalkylindole compounds and to signal a response through the inhibition of adenylate cyclase [7,15,42,66,70]. The mouse [64] and rat [22] CB₂ receptors have been cloned and exhibit 82% and 81% sequence identity, respectively to the human CB₂ receptor.

Cannabinoid CB₁ and CB₂ receptors are phylogenetically restricted to the chordate branch of the animal kingdom [52]. Among other established G protein-coupled receptors (GPCRs), those most closely related to CB₁/CB₂-type receptors are the lysophospholipid receptors S1P₁, S1P₂, S1P₃, S1P₄, S1P₅, LPA₁, LPA₂ and LPA₃. These receptors for endocannabinoids or lysophospholipid-like molecules have evolved independently in different branches of the GPCR superfamily but CB₁ and CB₂ are the only bona fide ‘cannabinoid receptors’ that have been identified to-date.

Molecular Biology

The coding sequence of the CB₁ receptor is contained in a single exon (see, for example, the human gene sequence Genbank accession U73304). However, an alternatively spliced form of the human receptor has been reported in which a 167 base portion of this exon is spliced out of the human mRNA leading to the predicted substitution of a different 28 residue sequence for the first 90aa [65]. This shorter mRNA appears to be relatively rare (< 20% of message by RT-PCR analysis), and the short isoform is likely to be inefficiently translated since it initiates at the second AUG of the mRNA and has a T rather than the highly preferred A or G at the critical -3 position of the Kozak consensus sequence. In both the rat and mouse genes, the invariant GT of the human splice donor site exists as a GA, which implies that this alternative splicing should not occur in these species. If the splice variant protein were expressed, the NC-IUPHAR guidelines dictate that the major, larger isoform should be termed CB_1(a) and the short isoform be referred to as CB_1(b). To date the short isoform has been referred to as CB_1A.

Functional characteristics of the CB₁ receptor

The CB₁ cannabinoid receptor has been extensively characterized for biological responses (see references [2,27] for review). Nervous system responses to Δ⁹-THC and other cannabinoid receptor agonists include therapeutically beneficial effects of analgesia, attenuation of the nausea and vomiting in cancer chemotherapy, appetite stimulation in wasting syndromes, and decreased intestinal motility. Untoward side effects accompanying these therapeutic responses include alterations in cognition and memory, dysphoria/euphoria and sedation. Animal models that distinguish cannabinoid receptor activity include drug discrimination paradigms in rodents, pigeons and primates, a typical static ataxia in dogs, and a tetrad of responses in rodents (hypothermia, analgesia, hypoactivity and catalepsy) [39]. Nerve-muscle tissue preparations (mouse vas deferens, mouse and guinea-pig ileum) respond to cannabinoid receptor agonists with an inhibition of contraction, believed to be the result of diminished release of neurotransmitter [54,60,76]. Indeed, it is now generally accepted that most CB₁ receptors are located at central or peripheral nerve terminals and that their main function is to mediate inhibition of on-going release of certain excitatory and inhibitory neurotransmitters [29,53,73]. These receptors are also expressed by some non-neuronal cells, for example immune cells [29].

CB₁ cannabinoid receptors are coupled to pertussis toxin (PTX)-sensitive G_i/G_o proteins in a manner that leads to the inhibition of adenylate cyclase activity [31,44], regulatation of L-, N- and P- or Q-type Ca²⁺ channels [19,34-35,74], and G protein-regulated A-type and inwardly rectifying K⁺ channels [11,24,35,52], an initiation of intracellular Ca²⁺ transients [71], a stimulation of mitogen-activated protein (MAP) kinase [71] and an induction of immediate early gene expression [6]. CB₁ receptors can also signal through G_s proteins [9,20,33,37].

In addition to orthosteric site(s), CB₁ receptors possess one or more allosteric sites with which some ligands can interact to enhance or inhibit CB₁ receptor activation by direct agonists [3,28,43,55]. There is also evidence that some CB₁ receptors form heteromers with dopamine D₂ receptors, μ-opioid receptors and orexin-1 receptors and that this heteromerization can affect CB₁ receptor activation by agonists [52]. These ‘CB-X receptor heteromers’ conform to the proposed conventions for structurally associated pairs in which the functional interactions influence ligand selectivity or relative intrinsic activity.

Functional characteristics of the CB₂ receptor

Most CB₂ receptors are expressed by immune cells located either outside or within the brain. When activated these receptors can modulate immune cell migration and cytokine release [8,29,48]. Cannabinoid CB₂ receptor mRNA can be found in spleen, tonsils, bone marrow, pancreas, splenic macrophage / monocyte preparations, peripheral blood leukocytes, and in a variety of cultured immune cell models including the myeloid cell line U937 and undifferentiated and differentiated granulocyte-like or macrophage-like HL60 cells [17,42]. CB₂ receptors may also be expressed by certain central and peripheral neurons [4-5,21,59,69,75,77]. However, the role of these putative neuronal receptors has yet to be established.

Signal transduction by the CB₂ receptor includes PTX-sensitive inhibition of cAMP production in transfected host CHO cells [15,22,70], MAP kinase activation and immediate early gene expression [7]. No modulation of ion channels or alterations of intracellular Ca²⁺ were observed in host cells expressing CB₂ receptors [15,70].

Pharmacology

K_i values derived from various ligand-binding assays and EC₅₀ values for a series of in vitro and in vivo activities have been compiled in several reviews [30,45-46,51-52,56,63].

Some cannabinoid receptor agonists activate CB₁ and CB₂ receptors with similar potency, although not always with similar intrinsic activity. These CB₁/CB₂ receptor agonists fall into one or other of four main chemical groups that have been named classical, nonclassical, aminoalkylindole and eicosanoid [29,46,48-52]. The classical group consists of dibenzopyran derivatives, two prominent members of which are (–)-Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the main psychoactive constituent of cannabis, and (–)-11-hydroxy-Δ⁸-tetrahydrocannabinol-dimethylheptyl (HU-210), a synthetic analogue of (–)-Δ⁸-tetrahydrocannabinol. The nonclassical group contains bicyclic and tricyclic analogues of Δ^9-THC that lack a pyran ring, a well-known member of this group being CP55940. The best known member of the aminoalkylindole group of CB₁/CB₂ receptor agonists is R-(+)-WIN55212, whilst two particularly notable members of the eicosanoid group are the endocannabinoids, anandamide and 2-arachidonoyl glycerol. Aminoalkylindoles and eicosanoids have structures that are markedly different both from each other and from classical and nonclassical cannabinoid receptor agonists.

Compounds that display markedly greater potency at activating CB₁ receptors than at activating CB₂ receptors have also been developed. The most notable of these CB₁-selective agonists are all synthetic analogues of anandamide: R-(+)-methanandamide, arachidonyl-2’-chloroethylamide (ACEA) and arachidonylcyclopropylamide (ACPA) [1,26]. Important CB₂-selective agonists include the classical cannabinoid, JWH-133, the nonclassical cannabinoid, HU-308, and the aminoalkylindoles, JWH-015 and AM1241 [29,46,48-49,51-52].

Several cannabinoid CB₁ and CB₂ receptor competitive antagonists have also been developed [16,29,46,49,51-52]. Antagonists that display significant CB₁-selectivity include rimonabant (SR141716A), AM251, AM281, LY320135 and taranabant. Importantly, these five compounds all behave as cannabinoid receptor inverse agonists as indicated by their ability to elicit responses in some CB₁ receptor-containing tissues that are opposite in direction from those induced by a CB₁ receptor agonist [16,47]. CB₁-selective competitive antagonists that lack any detectable ability to induce signs of inverse agonism at the CB₁ receptor when administered alone, thus behaving as ‘neutral’ antagonists, have also been discovered. These include NESS O327 and AM4113, both of which are structural analogues of rimonabant [61,68].

As to CB₂-selective competitive antagonists, those most often used as experimental tools are 6-iodopravadoline (AM630) and SR144528 [29,46,48-49,51-52]. Both these compounds behave as CB₂ receptor inverse agonists [57-58]. A neutral antagonist that selectively targets the CB₂ receptor has yet to be developed.

Non-CB₁/NON-CB₂ Receptor-mediated effects of Cannabinoid receptor ligands

It is now generally accepted that some endocannabinoids, including anandamide, 2-arachidonoyl glycerol and N-arachidonoyl dopamine, as well as Δ⁹-THC and a number of synthetic CB₁/CB₂ receptor agonists and antagonists can activate or block established non-CB₁, non-CB₂ GPCRs, ligand-gated ion channels, ion channels and/or nuclear receptors (PPAR receptors) [51-52]. Importantly, some cannabinoids seem to target these channels or receptors with potencies that differ little from those with which they activate or block CB₁ and/or CB₂ receptors. Anandamide, such example, displays such potency at T-type voltage-gated calcium channels, voltage-gated K_V3.1 and K_V4.3 potassium channels, calcium-activated potassium (BK) channels, NMDA receptors, glycine receptors, and allosteric sites on 5-HT₃ and nicotinic acetylcholine receptors [52].

Findings such as these strengthen the need to address the question of whether any known mammalian channel or non-CB₁, non-CB₂ receptor should be classified as a novel cannabinoid ‘CB₃’ receptor or channel. It is noteworthy, therefore, that the NC-IUPHAR cannabinoid receptor subcommittee has proposed five criteria that should be met by any such receptor or channel and come to the conclusion that, according to these five criteria, no channel, non-CB₁, non-CB₂ established receptor or deorphanized receptor should currently be classified or reclassified as a novel cannabinoid receptor [52]. However, it also considers that since the TRPV1 channel does appear to meet three of these criteria, at least in part, it may eventually come to be regarded as being either an ‘ionotropic cannabinoid CB₃ receptor’ or a dual TRPV1/CB₃ receptor that functions as a cannabinoid receptor when anandamide and/or other endocannabinoids are released onto it in high amounts under pathological conditions [52].

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